CCL5-dependent mast cell infiltration into the tumor microenvironment in clear cell renal cell carcinoma patients

We investigated the mechanisms affecting tumor progression and survival outcomes in Polybromo-1 -mutated ( PBRM1 MUT ) clear cell renal cell carcinoma (ccRCC) patients. PBRM1 MUT ccRCC tissues contained higher numbers of mast cells and lower numbers of CD8 + and CD4 + T cells than tissues from PBRM1 WT ccRCC patients. Hierarchical clustering, pathway enrichment and GSEA analyses demonstrated that PBRM1 mutations promote tumor progression by activating hypoxia inducible factor (HIF)-related signaling pathways and increasing expression of vascular endothelial growth factor family genes. PBRM1 MUT ccRCC tissues also show increased expression of C-C motif chemokine ligand 5 (CCL5). PBRM1-silenced ccRCC cells exhibited greater Matrigel tube formation and cell proliferation than controls. In addition, HMC-1 human mast cells exhibited CCL5-dependent in vitro migration on Transwell plates. High CCL5 expression in PBRM1 MUT ccRCC patients correlated with increased expression of genes encoding IFN-γ, IFN-α, IL-6, JAK-STAT3, TNF-α, and NF-ΚB. Moreover, high CCL5 expression was associated with poorer survival outcomes in ccRCC patients. These findings demonstrate that CCL5-dependent mast cell infiltration promotes immunosuppression within the tumor microenvironment, resulting in tumor progression and adverse survival outcomes in PBRM1 MUT ccRCC patients.